CN109662968A - The liter white preparation of -5 α androstane hydride compounds of carbon loss containing A- and its application - Google Patents

The liter white preparation of -5 α androstane hydride compounds of carbon loss containing A- and its application Download PDF

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CN109662968A
CN109662968A CN201710953300.5A CN201710953300A CN109662968A CN 109662968 A CN109662968 A CN 109662968A CN 201710953300 A CN201710953300 A CN 201710953300A CN 109662968 A CN109662968 A CN 109662968A
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androstane
bis
carbon loss
hydride compounds
active constituent
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CN109662968B (en
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陈雅君
谌志华
王文雅
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SHANGHAI AOQI MEDICAL TECHNOLOGY CO LTD
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SHANGHAI AOQI MEDICAL TECHNOLOGY CO LTD
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Priority to PCT/CN2018/100430 priority patent/WO2019072014A1/en
Priority to AU2018348892A priority patent/AU2018348892B2/en
Priority to JP2020541841A priority patent/JP7123431B2/en
Priority to CA3079031A priority patent/CA3079031C/en
Priority to US16/755,698 priority patent/US20200289527A1/en
Priority to EP18866348.8A priority patent/EP3692994A4/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

The present invention provides the liter white preparation of -5 α androstane hydride compounds of carbon loss containing A- and its applications.Specifically, the present invention provides a kind of purposes of -5 α androstane hydride compounds of A- carbon loss, are used to prepare a preparation or composition, the preparation or composition (a) are for promoting quantity of leucocyte；Or (b) for preventing or treating leukopenia.- 5 α androstane hydride compounds of A- carbon loss can be relieved and improve the reduction of leukocyte count caused by anti-tumor drug (such as chemotherapeutics such as cyclophosphamide) or radiotherapy, significant in efficacy, Small side effects, easy to use.In addition, giving A- carbon loss -5 α androstane hydride compounds before carrying out chemotherapy or radiotherapy, the decline of leukocyte count can be prevented, do not significantly reduced in a long time.

Description

The liter white preparation of -5 α androstane hydride compounds of carbon loss containing A- and its application
Technical field
The invention belongs to field of medicaments, liter white preparation more particularly to -5 α androstane hydride compounds of carbon loss containing A- and its answer With.
Background technique
Leukopenia refers to when the white blood cell count(WBC) in the peripheral blood of people is consistently less than 4.0 × 109/ L or less.Generally make Leukocytoblast, which reduces disease reason, drug, radioactive ray or other chemical toxicants.Oligoleukocythemia will lead to hypoimmunity, appetite Decline, the symptoms such as limbs fatigue.
Currently, chemotherapy and radiation is the means of common oncotherapy.However, chemotherapy and radiation can frequently result in leucocyte It reduces, while killing cancer cell, can also damage normal tissue, especially to inhibit the most obvious to hemopoietic function of bone marrow, cause Peripheral leukocytes persistently reduce.This situation not only hinders continuing for chemotherapy and radiation, and can cause serious consequence.
Clinically put patient to increase number of white blood cells in blood samples of patients commonly using some shengbai drugs at present Chemotherapy can be gone on smoothly as scheduled, guarantee the cycle therapy of chemicotherapy.These shengbai drugs specifically include that 1, Chinese herbal medicine, such as: people Ginseng, Radix Astragali, Radix Codonopsis, the fruit of glossy privet, Caulis Spatholobi, fructus lycii, glutinous rehmannia etc.；2, compound Chinese medicinal preparation, such as dull-witted soup, Bao Yuan Tang, Six-element Rehmannia-root oral liquid, the white ball of liter, White Phoenix Bolus of Black-bone Chicken, JIANPI YISHEN CHONGJI, the white electuary of Chang'an liter, rising white tiles, SHENQI PIAN, blood-nourishing liter are white Capsule etc.；3, chemicals, such as leucogen, batyl alcohol, vitamin B, Berbamine, inosine, DNA；4, biology system Agent, such as colony stimulating factor (CSF), granulocyte colony stimulating factor (GCSF), granulocyte-macrophage colony stimutaing factor (GMCSF) etc..Wherein the curative effect of preceding 3 class Chinese and western drugs is all relatively limited, although hematopoiesis stimulating factors significant effect, when acting on Between it is short, be easy to repeatedly, side effect is obvious, and expensive, and patient economy burden is larger.
Therefore, there is an urgent need to develop significant in efficacy, Small side effects, the medicine of increasing leukocyte easy to use for this field clinic Object.
Summary of the invention
It is an object of the invention to provide a kind of significant in efficacy, Small side effects, the drug of increasing leukocyte easy to use.
In the first aspect of the present invention, a kind of purposes of -5 α androstane hydride compounds of A- carbon loss is provided, a system is used to prepare Agent or composition, the preparation or composition (a) are for promoting quantity of leucocyte；Or it (b) is used to prevent or treat leucocyte to subtract Few disease.
In another preferred example, the structure of -5 α androstane hydride compounds of A- carbon loss is shown in formula I:
In formula,
R1And R2It is each independently selected from: H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C3-8Naphthenic base, Substituted or unsubstituted phenyl ring, substituted or unsubstituted benzoyl, substituted or unsubstituted COCnH2n+1, it is substituted or unsubstituted COCrH2rCOOCmH2m+1Or-COCpH2pCOO-W；Wherein, n, p, r, m are each independently 0~18 integer, W H, Na+、 K+、NH4 +、1/2Ca2+、1/2Mg2+、1/2(AlOH)2+Or 1/2Zn2+,
The substitution, which refers to, has one or more (such as 1-3) substituent group selected from the group below: hydroxyl, halogen, nitro, Amino, amido, carboxyl.
In another preferred example, -5 α androstane hydride compounds of A- carbon loss are selected from the group:
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls diacetate compound；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls double propionate compound；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β--2 β of bis- hydroxyls-monosuccinic acid ester compounds；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- succinate compounds；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- butyric acid ester compounds；
2 α, 17 α--5 α of bis- hydroxypropyl alkynyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；
- 5 α of 2 α, 17 α-dicyanogen methyl isophorone-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；
The double trichloroacetic acid ester compounds of 2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β--17 β succinate of -2 β of bis- hydroxyls-propionic ester Compound；
2 α, 17 α--5 α of bis- propinyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；And/or
2 α, 17 α--5 α of bis- propinyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls double propionate compound.
In another preferred example, the composition is pharmaceutical composition, dietary supplement compositions or Halth-care composition.
In another preferred example, the composition includes -5 α androstane hydride compounds of (a) A- carbon loss；(b) it can pharmaceutically connect The carrier received.
In another preferred example, the dosage form of the pharmaceutical composition is solid pharmaceutical preparation or liquid preparation.
In another preferred example, the dosage form of the pharmaceutical composition is peroral dosage form, injection or externally applied drug agent Type.
In another preferred example, the pharmaceutical composition is tablet, granule or capsule.
In another preferred example, contain 0.001-99wt% in the preparation or composition, preferably 0.1-90wt%, more - 5 α androstane hydride compounds of A- carbon loss of good ground 1-50wt%, by the total weight of preparation or composition.
In another preferred example, described " promoted quantity of leucocyte " instigate in the blood middle leukocytes quantity of an object It rises.
In another preferred example, object behaviour or non-human mammal (such as rodent).
In another preferred example, the object is the people of quantity of leucocyte decline.
In another preferred example, " the quantity of leucocyte decline " refers to the lower limit A0 phase with the quantity of leucocyte of normal person Than the quantity of leucocyte A1 of the object is lower than A0；Preferably, A1/A0 is 0.1-0.9, preferably 0.2-0.8, more preferably 0.3-0.7。
In another preferred example, the A0 is 4 × 109A/L blood.
In another preferred example, the object is tumor patient.
In another preferred example, the object is, or will receive the object of oncotherapy.
In another preferred example, the oncotherapy include: chemotherapy, radiotherapy, or combinations thereof.
In another preferred example, described " promoting quantity of leucocyte " refers to, compared with the quantity of leucocyte C0 of control, so that one The blood middle leukocytes quantity C1 of object increases.
In another preferred example, the quantity of leucocyte C0 of the control is that the object is controlled with drug of the present invention Quantity of leucocyte Czs before treating or handling；Or the quantity of leucocyte Cdz for control group.
In another preferred example, described " promoting quantity of leucocyte " refers to C1/Czs >=1.2, preferably >=1.4, more preferably >= 1.5 or >=2.0.
In another preferred example, described " promoting quantity of leucocyte " refers to C1/Cdz >=1.2, preferably >=1.4, more preferably >= 1.5 or >=2.0.
In the second aspect of the present invention, a kind of system for promoting quantity of leucocyte or preventing and treating leukopenia is provided Agent product, the formulation products include:
First pharmaceutical composition, first pharmaceutical composition contain (a) first active constituent, first active constituent For -5 α androstane hydride compounds of A- carbon loss；(b) pharmaceutically acceptable carrier；And
Second pharmaceutical composition, second pharmaceutical composition are shengbai drug.
In another preferred example, the shengbai drug contains (a) second active constituent, and second active constituent is not It is same as the white active constituent of liter of -5 α androstane hydride compounds of A- carbon loss；(b) pharmaceutically acceptable carrier.
In another preferred example, the quantity of leucocyte that promoted is the leukocyte count for promoting mammal.
In another preferred example, the shengbai drug is selected from the group: Chinese herbal medicine, compound Chinese medicinal preparation, chemicals, biology Preparation, or combinations thereof.
In another preferred example, the Chinese herbal medicine is selected from the group: ginseng, Radix Astragali, Radix Codonopsis, the fruit of glossy privet, Caulis Spatholobi, fructus lycii Son, glutinous rehmannia, or combinations thereof.
In another preferred example, the compound Chinese medicinal preparation is selected from the group: dull-witted soup, Bao Yuan Tang, Liuweidihuang Oral Liquid, Rise white ball, White Phoenix Bolus of Black-bone Chicken, JIANPI YISHEN CHONGJI, the white electuary of Chang'an liter, rising white tiles, SHENQI PIAN, blood-nourishing paste capsule of rising white blood cell or its group It closes.
In another preferred example, the chemicals are selected from the group: leucogen, batyl alcohol, vitamin B, Berbamine, flesh Glycosides, DNA, or combinations thereof.
In another preferred example, the biological agent is selected from the group: colony stimulating factor (CSF), granular leukocyte colony stimulation The factor (G-CSF), granulocyte-macrophage colony stimutaing factor (GM-CSF), or combinations thereof.
In another preferred example, first pharmaceutical composition and the second pharmaceutical composition are independent or close Two be one.
In the third aspect of the present invention, provide a kind of for treating the formulation products of tumour, the formulation products include:
(I) I pharmaceutical composition, the I pharmaceutical composition contain (a) I active constituent, first active constituent For -5 α androstane hydride compounds of A- carbon loss；(b) pharmaceutically acceptable carrier；And
(II) Section II pharmaceutical composition, the Section II pharmaceutical composition contain (a) Section II active constituent, and described second is living Property ingredient be different from A- carbon loss -5 α androstane hydride compounds for treating the active constituent of tumour；(b) pharmaceutically acceptable Carrier.
In another preferred example, the Section II active constituent is selected from the group: cyclophosphamide, ifosfamide, how western fluorine Bird pyridine, 5 FU 5 fluorouracil, cytarabine, fluorine guanosine, Tegafur, gemcitabine, Carmofur, hydroxycarbamide, methotrexate (MTX), actinomyces Plain D, adriamycin, daunorubicin, epirubicin, mitomycin, Peplomycin, Irinotecan, harringtonine, hydroxy-camptothecin Alkali, taxol, taxotere, topotecan, vincristine, eldisine, Vindesine, Teniposide, relies on pool at Vinorelbine His progesterone, tamoxifen, L-Asparaginasum, card of glycosides, atamestane, Anastrozole, aminoglutethimide, Letrozole, formestane, first Platinum, cis-platinum, Dacarbazine, oxaliplatin, mitoxantrone, procarbazine.
In another preferred example, first pharmaceutical composition and the second pharmaceutical composition are independent or close Two be one.
In the fourth aspect of the present invention, a kind of method for promoting quantity of leucocyte is provided, comprising steps of (a) is to needs Object apply -5 α androstane hydride compounds of A- carbon loss.
In another preferred example, the object includes people or non-human mammal, and it is (such as small to be preferably comprised rodent Mouse, rat), Primate (such as people).
In another preferred example, the object is tumor patient.
In another preferred example, the tumour is selected from the group: gastric cancer, liver cancer, leukaemia, tumor of kidney, lung cancer, small intestine Cancer, osteocarcinoma, prostate cancer, colorectal cancer, breast cancer, colorectal cancer, prostate cancer, cervical carcinoma, lymph cancer, adrenal tumor or Tumor of bladder.
In another preferred example, the object be, or will receive chemotherapy and/or radiotherapy.
In another preferred example, the object receives chemotherapy or radiotherapy.
In another preferred example, the leukocyte count of the object is lower than lower limits of normal.
In another preferred example, the object receives chemotherapy or radiotherapy and leukocyte count are near or below under normal value Limit.
In another preferred example, when the object is people, the range of normal value is 4 × 109-10×109/L。
In another preferred example, it is white thin before being carried out rising white treatment with the method for the present invention when the object is people Born of the same parents' number is 1 × 109-3.8×109/L。
In another preferred example, when the object is mouse, the normal value is 1.8 × 103-10.7×103/uL。
In another preferred example, the method is non-therapeutic.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific embodiment
The present inventor after extensive and in-depth study, for the first time it was unexpectedly observed that the special compound-i.e. A- of a class formation - 5 α androstane hydride compounds of carbon loss can effectively promote the quantity of leucocyte of mammal, and its side effect is very low. Experiment shows to be relieved and improve the drop of leukocyte count caused by anti-tumor drug (such as chemotherapeutics such as cyclophosphamide) or radiotherapy It is low.In addition, giving A- carbon loss -5 α androstane hydride compounds before carrying out chemotherapy or radiotherapy, the decline of leukocyte count can be prevented, It is not significantly reduced in long period.On this basis, the present invention is completed.
Active component
In the present invention, for rising, white active component is -5 α androstane hydride compounds of A- carbon loss or its is pharmaceutically acceptable Salt or prodrug.
- 5 α androstane hydride compounds of A- carbon loss are that one kind of Li Ruilin et al. independent research synthesis has the chemical combination of special construction Object.Existing animal efficacy test shows that -5 α androstane hydride compounds of A- carbon loss have preferable treatment hyperplasia of prostate effect.? Further discovery -5 α androstane hydride compounds of A- carbon loss have significant anti-malignant tumor activity in vivo and in vitro in research, inhibit With the advantage for improving the weight of animals reduction while tumor proliferation.It is selectively prevented under the premise of not influencing normal cell swollen The division of oncocyte, to inhibit the diffusion of tumour cell.
Present inventors have surprisingly found that -5 α androstane hydride compounds of A- carbon loss have unexpectedly significantly rises white drug effect.
In the present invention, term " active component ", " inventive compound ", " the white active constituent of liter of the invention " are interchangeable It uses, refers to -5 α androstane hydride compounds of A- carbon loss, the compound especially having the following structure:
In formula, R1And R2As defined above.
Preferably, -5 α androstane hydride compounds of A- carbon loss can be one or more compounds selected from the group below:
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound (Ia)；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls diacetate compound (Ib)；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls double propionate compound (Ic)；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β--2 β of bis- hydroxyls-monosuccinic acid ester compounds (Id)；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- succinate compounds (Ie)；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- butyric acid ester compounds (If)；
2 α, 17 α--5 α of bis- hydroxypropyl alkynyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound (Ig)；
- 5 α of 2 α, 17 α-dicyanogen methyl isophorone-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound (Ih)；
The double trichloroacetic acid ester compounds (Ii) of 2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β--17 β succinate of -2 β of bis- hydroxyls-propionic ester Compound (Ij)；
2 α, 17 α--5 α of bis- propinyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound (Ik)；Or
2 α, 17 α--5 α of bis- propinyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls double propionate compound (Il).
Pharmaceutical composition
The present invention provides a kind of for promoting the pharmaceutical composition of quantity of leucocyte, and described pharmaceutical composition includes (a) A- - 5 α androstane hydride compounds of carbon loss；(b) acceptable carrier in pharmaceutically acceptable carrier or bromatology.
" active constituent " in pharmaceutical composition of the present invention refers to formula of the present invention (I) compound.
" active constituent " of the present invention and pharmaceutical composition can be used for promoting quantity of leucocyte.
In another preferred example, it is used to prepare shengbai drug.
" safe and effective amount " refers to: the amount of active constituent is enough to be obviously improved the state of an illness, and is unlikely to generate serious pair Effect.
In general, pharmaceutical composition contains 1-2000mg active constituent/agent, more preferably, containing 10-200mg active constituent/ Agent.Preferably, described is " one " for a tablet or an injection.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass, They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity.
In " compatibility " referred to herein as composition each component energy and active constituent of the invention and they between mutually Blending, and significantly reduce the drug effect of active constituent.
Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl Sodium cellulosate, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, plant Oily (such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsification AgentWetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, nothing Pyrogen water etc..
In another preferred example, formula (I) compound of the present invention can pass through nonbonding cooperation with macromolecular compound or macromolecule With formation compound.
In another preferred example, formula (I) compound of the present invention can also pass through chemical bond and macromolecular chemical combination as small molecule Object or macromolecule are connected.The macromolecular compound can be large biological molecule such as high glycan, albumen, nucleic acid, polypeptide etc..
The method of application of active constituent or pharmaceutical composition of the invention is not particularly limited, representative method of application packet It includes but is not limited to: in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) etc..
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.
In these solid dosage forms, active constituent is mixed at least one conventional inert excipients or carrier, such as citric acid Sodium or Dicalcium Phosphate, or with following compositions are one or more mixes:
(a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；
(b) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arab Glue；
(c) moisturizer, for example, glycerol；
(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；
(e) retarding solvent, such as paraffin；
(f) absorbsion accelerator, for example, quaternary ammonium compound；
(g) wetting agent, such as cetanol and glycerin monostearate；
(h) adsorbent, for example, kaolin；And/or
(i) lubricant, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate, or Its mixture.
In capsule, tablet and pill, dosage form also may include buffer.
Coating and shell material preparation also can be used in the solid dosage forms, such as casing and other materials well known in the art.It May include opacifying agent, also, in this composition active constituent release can in a delayed fashion it is in the digestive tract certain It is discharged in a part.The example of adoptable embedding component is polymeric material and wax material.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. Other than active constituent, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, solubilising Agent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide And oil, the especially mixture of cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweetener, rectify Taste agent and fragrance.
Other than active constituent, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene mountain The pure and mild Isosorbide Dinitrate of pears, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 1~1000mg, preferably 10~200mg, more preferably 20~100mg.Certainly, specific dosage is also contemplated that administration way The factors such as diameter, patient health situation, within the scope of these are all skilled practitioners technical ability.
The compounds of this invention can be administered alone, or with other treatment drug (especially anticarcinogen or shengbai drug) It is administered in combination.
Formula (I) compound can also be combined to the known other medicines for treating or improving similar symptom.When administering drug combinations, Originally the administration mode of drug and dosage remain unchanged, and subsequently or simultaneously take formula (I) compound.When formula (I) compound with When other one or more drugs are taken simultaneously, it is preferable to use simultaneously containing one or more of known drugs and formula (I) compound Pharmaceutical composition.The period that drug combination is also included within overlapping takes known to formula (I) compound and other one or more Drug.When formula (I) compound and other one or more of drugs carry out drug combination, formula (I) compound or known drug Dosage when dosage may be than their independent medications is lower.
Oral preparation
The present invention provides the oral preparation that a kind of active component is -5 α androstane hydride compounds of A- carbon loss, by grinding before prescription Study carefully and provides foundation for the research of pharmaceutical preparation.
Preformulation study the result shows that: -5 α androstane hydride compounds of water-insoluble drug A- carbon loss (in water solubility be 6.5 Micrograms per millilitre is insoluble by pharmacopoeial definitions.) have preferable dissolution in intestinal juice and absorb, transhipment in vivo, intake and Mechanism of absorption is Passive diffusion, and time and dose dependent is presented in intake.- 5 α androstane hydride compounds of A- carbon loss can lead to Cross oral administration.And since the treatment of cancer needs Long-term taking medicine, oral administration is convenient, and complying with for patient can be improved Property, therefore the present invention is designed to oral preparation, such as normal oral tablet, oral capsule and other sustained-release preparations.
The parts by weight of oral preparation of the invention, component and each component are as follows:
The active component is -5 α androstane hydride compounds of A- carbon loss；
Added filler can be one or several kinds of ingredients for increasing tablet weight and volume.In the present invention, institute State filler be selected from one of lactose, sucrose, sorbierite, mannitol, polyethylene glycol, starch and inorganic salts or two kinds with On.The dosage of the filler accounts for the 20-95% of preparation total amount, preferably 60-95%, more preferably 70-95%, most preferably 80- 95%.When lactose is as filler, the dosage of lactose accounts for the 20-95% of preparation total amount, when sucrose is as filler, sucrose Dosage accounts for the 10-30% of preparation total amount, and when sorbierite is as filler, the dosage of sorbierite accounts for the 20-95% of preparation total amount, sweet When revealing alcohol as filler, the dosage of mannitol accounts for the 20-95% of preparation total amount, when inorganic salts are as filler, inorganic salts Dosage accounts for the 5-20% of preparation total amount.In another preferred example, the filler be lactose, mannitol, sorbierite or they Mixture；Preferably, the filler is the mixture of lactose and mannitol.
The disintegrating agent is selected from crospovidone (PVPP), croscarmellose sodium (CC Na), carboxymethyl starch One of sodium (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC) are two or more, wherein being with PVPP and CC Na It is good, most preferably CC Na.The amount ranges (with gross weight ratio) of disintegrating agent are 0-20%, and general dosage is 1-10%, most preferably 3- 5%.
The lubricant is selected from stearic acid, odium stearate, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oil One of or it is two or more, wherein most appropriate with magnesium stearate.The amount ranges (with gross weight ratio) of lubricant are 0.1- 5%, general dosage is 0.2-4%, most preferably 0.3-3%.
Used adhesive can be one or more of ingredients for being conducive to granulation.The adhesive is selected from starch One of slurry, hydroxypropyl methyl cellulose (HPMC), polyethylene glycol, povidone (PVP) or copolyvidone (Kollidon) or Person is two or more.It is preferred that PVP.When starch slurry is as adhesive, the dosage of starch slurry accounts for the 10-30% of preparation total amount, when When HPMC is as adhesive, the dosage of HPMC accounts for the 2-5% of preparation total amount, and when PVP is as adhesive, the dosage of PVP accounts for system The 2-20% of agent total amount, when povidone is as adhesive, the dosage of copolyvidone accounts for the 0.1-10% of preparation total amount.
The glidant is selected from one of superfine silica gel powder and talcum powder or two kinds, more preferably superfine silica gel powder.
In another preferred example, the inorganic salts are selected from: calcium sulfate (crystallization water containing two molecules)；Calcium monohydrogen phosphate；Medicine With calcium carbonate etc..
Typically, Tablets can also contain the auxiliary material well known to those skilled in the art that other are readily conceivable that, this The preparation of invention tablet can use technology of preparing well known in the art.Such as when preparing tablet, can using direct compression method, Wet granulation tableting, compressing dry granulation.
The present invention provides a kind of conventional tablet of -5 α androstane hydride compounds of A- carbon loss, according to its of pharmacodynamic study determination Clinical administration dosage determines that -5 α androstane compound tablet specification of A- carbon loss is 1-100mg/ to meet clinical treatment needs Piece, preferably, being 1-50mg/ piece, such as 2.5mg/ piece, 5mg/ piece, 10mg/ piece, 25mg/ piece.
Main advantages of the present invention include:
(a) present invention, which rises white active constituent (i.e. -5 α androstane hydride compounds of A- carbon loss), can effectively promote lactation The quantity of leucocyte of animal.
(b) side effect of the white active constituent of present invention liter is very low.
(c) on the one hand liter white effect of the invention not will lead to quantity of leucocyte and excessively increase (i.e. without departing from normal value The upper limit), it on the other hand can maintain for a long time, a liter white effect this in a long time does not significantly reduce.
(d) inventive compound can be not only used for treatment leukopenia, it may also be used for prevention oligoleukocythemia Disease.
(e) inventive compound and other oncotherapy means (such as chemotherapy) are combined, can further lowers it The side effect of his chemotherapeutic simultaneously enhances treatment therapeutic effect, has synergistic effect.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.
Material
ACP1:2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls diacetate compound (Ib)
ACP2:2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β--2 β of bis- hydroxyls-monosuccinic acid esterification are closed Object (Id)
ACP3:2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- butyric acid ester compounds (If)
ACP4:2 α, 17 α--5 α of bis- propinyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound (Ik)
ACP5:2 α, 17 α--5 α of bis- propinyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls double propionate compound (Il)
The leukogenic effect that embodiment 1ACP causes Lewis murine interleukin number to reduce to cyclophosphamide (CTX)
The leukogenic effect of 1.1ACP1
Eugonic tumour is taken, a homogenate method is prepared into cell suspension about 5-10 × 10 under aseptic condition6/ ml tumour is thin Born of the same parents' concentration.Every mouse right axillary inoculates 0.2ml.
Mouse is caused transplanted tumor model and be grouped at random, every group of 10 animals with the inoculation of Lewis lung cancer, and in connecing The kind tumour same day, which starts to give, rises white compound.In addition to the simple ACP1 administration group of high dose, remaining each group was in inoculation the 3rd day (150mg/kg) and the 5th day (100mg/kg) application CTX causes chemotherapy that tumor-bearing mice oligoleukocythemia is caused to inhibit model.
Experiment takes 10 mouse to carry out retroorbital venous clump puncture blood collecting, haemocyte automatic analyzer at random when starting (HEMAVET-950) blood routine is tested.Hereafter, cyclophosphamide after the last administration, the 8th day and the 12nd day press same procedure Blood sampling test blood routine.
The results are shown in Table 1 by ACP1.
1 ACP1 sample of table combines liter white test of the cyclophosphamide to lotus Lewis lung cancer in mice
Note: compared with chemotherapeutical control group: * P < 0.05；(data in literature: the range of normal value 1.8 of murine interleukin × 103-10.7×103/uL)
As a result:
In chemotherapeutical control group, cyclophosphamide CTX causes the reduction of mouse peripheral blood leucocyte, shows oligoleukocythemia The modeling success of the animal pattern of disease.
In ACP administration group, statistically significant liter white effect is shown the 8th day and the 12nd day, with chemotherapy pair It is compared according to group, it was 60% to about 100% at the 12nd day that rising white amplitude, which was about 200% to about 500% to differ at the 8th day,.This table Bright, ACP1 plays the role of apparent antagonism cyclophosphamide and murine interleukin number is caused to reduce.
The leukogenic effect of 1.2 ACP2-5
With 1.1, difference is method: each group of mouse quantity is 5；In experimental group, respectively with ACP2, ACP3, ACP4 and ACP5 replace ACP1 respectively, and only with the scheme of ACP middle dosage+CTX 2.5mg/kg；Chemotherapeutical control Chemotherapeutical control group in group same 1.1.At the 10th day by same procedure blood sampling test blood routine.
The experimental results showed that cyclophosphamide CTX causes the reduction of mouse peripheral blood leucocyte in chemotherapeutical control group, Show the modeling success of the animal pattern of leukopenia.
In each ACP administration group, statistically significant liter white effect was shown at the 10th day, with chemotherapeutical control group phase Than the white amplitude of the liter of ACP2, ACP3, ACP4 and ACP5 is suitable, and the white amplitude of liter ((C1/Cdz-100%)) at the 10th day exists In 70% to 240% range.This shows that -5 α androstane hydride compounds of A- carbon loss all have apparent antagonism cyclophosphamide and cause mouse The effect that leukocyte count reduces.
Above-mentioned experimental result prompt, the present invention rise white active constituent and are relieved and improve anti-tumor drug (such as ring phosphorus Amide) caused by leukocyte count reduce, so as to for preventing and/or treat leukopenia.
2 ACP1 of embodiment is to the white test of the liter of tumor patient
Receive chemotherapy that (chemotherapeutics used has doxorubicin, cyclophosphamide, Irinotecan, taxol, suitable with 10 Platinum, oxaliplatin, vincristine, fluorouracil etc.) and peripheral blood in number of white blood cells reduced tumor patient conduct occurs Subject.It takes a blood sample within (the 0th day) on the day before medication, blood routine is tested, as white before being treated with drug of the present invention Cell quantity (Czs).
10 subjects take ACP (being shown in Table 2) daily with different medicining times and dosage, respectively 8 days, 15 days, 22 It took a blood sample to 10 subjects with 28 days, tested blood routine.
The results are shown in Table 2.
2 ACP1 of table is to the white test of the liter of tumor patient
Note: white blood cell count(WBC) (WBC) range of normal value: 4 × 109-10×109/L
The result shows that ACP1 is obviously improved quantity of leucocyte.
(i) after the tablet has been ingested the 8th day when, the leukocyte count (C1/Czs) of most subjects significantly increased (with rise it is white It is compared before processing, leucocyte ascensional range (C1/Czs-100%)=about 50%).
(ii) after the tablet has been ingested the 15th day when, the leucocyte (C1/Czs) of subject is further up, promoted amplitude averagely about 80%, up to about 178%.
(iii) when the 22nd day after taking medicine, the leucocyte of subject promotes amplitude averagely about 63%.
(iv) after the tablet has been ingested the 28th day when, the leucocyte of subject promotes amplitude averagely about 50%.In entire inspection in 28 days In the survey phase, the leukocyte count of subject is not substantially reduced, maintains normal white cell level.
Therefore, the compounds of this invention can be obviously improved the number of white blood cells of tumor patient, have significant leukogenic effect.
This prompt (is near or below white for carrying out chemotherapy with anti-tumor drug so as to cause leukocyte count decline Cell lower limits of normal) object, the present invention rises white active constituent and is significantly improved, so as to for treat chemotherapy (or Radiotherapy) caused by oligoleukocythemia.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. a kind of purposes of -5 α androstane hydride compounds of A- carbon loss, which is characterized in that it is used to prepare a preparation or composition, it is described Preparation or composition (a) are for promoting quantity of leucocyte；Or (b) for preventing or treating leukopenia.
2. purposes as described in claim 1, which is characterized in that the structure such as Formulas I institute of -5 α androstane hydride compounds of A- carbon loss Show:
In formula,
R1And R2It is each independently selected from: H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C3-8Naphthenic base, substitution Or unsubstituted phenyl ring, substituted or unsubstituted benzoyl, substituted or unsubstituted COCnH2n+1, it is substituted or unsubstituted COCrH2rCOOCmH2m+1Or-COCpH2pCOO-W；Wherein, n, p, r, m are each independently 0~18 integer, W H, Na+、K+、NH4 +、1/2Ca2+、1/2Mg2+、1/2(AlOH)2+Or 1/2Zn2+,
The substitution, which refers to, has one or more (such as 1-3) substituent group selected from the group below: hydroxyl, halogen, nitro, ammonia Base, amido, carboxyl.
3. purposes as described in claim 1, which is characterized in that -5 α androstane hydride compounds of A- carbon loss are selected from the group:
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls diacetate compound；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls double propionate compound；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β--2 β of bis- hydroxyls-monosuccinic acid ester compounds；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- succinate compounds；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- butyric acid ester compounds；
2 α, 17 α--5 α of bis- hydroxypropyl alkynyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；
- 5 α of 2 α, 17 α-dicyanogen methyl isophorone-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；
The double trichloroacetic acid ester compounds of 2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls；
2 α, 17 α--5 α of bis- acetenyls-A- carbon loss-androstane -2 β, 17 β--17 β succinate chemical combination of -2 β of bis- hydroxyls-propionic ester Object；
2 α, 17 α--5 α of bis- propinyls-A- carbon loss--2 β of androstane, 17 β-dihydroxyl compound；And/or
2 α, 17 α--5 α of bis- propinyls-A- carbon loss-androstane -2 β, 17 β-bis- hydroxyls double propionate compound.
4. purposes as described in claim 1, which is characterized in that contain 0.001-99wt% in the preparation or composition, compared with - 5 α androstane hydride compounds of A- carbon loss of good ground 0.1-90wt%, more preferably 1-50wt%, by the total weight of preparation or composition Meter.
5. a kind of formulation products for promoting quantity of leucocyte or preventing and treating leukopenia, which is characterized in that the preparation Product includes:
First pharmaceutical composition, first pharmaceutical composition contain (a) first active constituent, and first active constituent is A- - 5 α androstane hydride compounds of carbon loss；(b) pharmaceutically acceptable carrier；And
Second pharmaceutical composition, second pharmaceutical composition are shengbai drug.
6. formulation products as claimed in claim 5, which is characterized in that the shengbai drug contains (a) second active constituent, Second active constituent is the white active constituent of liter different from -5 α androstane hydride compounds of A- carbon loss；(b) pharmaceutically acceptable Carrier.
7. formulation products as claimed in claim 5, which is characterized in that the shengbai drug is selected from the group: Chinese herbal medicine, Chinese medicine are multiple Square preparation, chemicals, biological agent, or combinations thereof.
8. a kind of for treating the formulation products of tumour, which is characterized in that the formulation products include:
(I) I pharmaceutical composition, the I pharmaceutical composition contain (a) I active constituent, and first active constituent is A- - 5 α androstane hydride compounds of carbon loss；(b) pharmaceutically acceptable carrier；And
(II) Section II pharmaceutical composition, the Section II pharmaceutical composition contain (a) Section II active constituent, second activity at It is divided into different from -5 α androstane hydride compounds of A- carbon loss for treating the active constituent of tumour；(b) pharmaceutically acceptable load Body.
9. formulation products as claimed in claim 8, which is characterized in that the Section II active constituent is selected from the group: ring phosphinylidyne Amine, ifosfamide, how western fluorine bird pyridine, 5 FU 5 fluorouracil, cytarabine, fluorine guanosine, Tegafur, gemcitabine, Carmofur, hydroxyl Base urea, methotrexate (MTX), actinomycin D, adriamycin, daunorubicin, epirubicin, mitomycin, Peplomycin, Irinotecan, Harringtonine, hydroxycamptothecin, Vinorelbine, taxol, taxotere, topotecan, vincristine, eldisine, Changchun Amide, Teniposide, Etoposide, atamestane, Anastrozole, aminoglutethimide, Letrozole, formestane, first his progesterone, he not Former times sweet smell, L-Asparaginasum, carboplatin, cis-platinum, Dacarbazine, oxaliplatin, mitoxantrone, procarbazine.
10. a kind of method for promoting quantity of leucocyte, which is characterized in that comprising steps of (a) loses to the object application A- needed - 5 α androstane hydride compounds of carbon.
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AU2018348892A AU2018348892B2 (en) 2017-10-13 2018-08-14 Formulation containing A-decarbonized-5a androstane compound for increasing white blood cell and use thereof
JP2020541841A JP7123431B2 (en) 2017-10-13 2018-08-14 Leukocytosis preparation containing A-nor-5αandrostane compound and use thereof
CA3079031A CA3079031C (en) 2017-10-13 2018-08-14 Formulation containing a-decarbonized-5-alpha androstane compound for increasing white blood cell and use thereof
PCT/CN2018/100430 WO2019072014A1 (en) 2017-10-13 2018-08-14 FORMULATION CONTAINING A-DECARBONIZED-5α ANDROSTANE COMPOUND FOR INCREASING WHITE BLOOD CELL AND USE THEREOF
US16/755,698 US20200289527A1 (en) 2017-10-13 2018-08-14 FORMULATION CONTAINING A-DECARBONIZED-5a ANDROSTANE COMPOUND FOR INCREASING WHITE BLOOD CELL AND USE THEREOF
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